Sexually transmitted diseases (STDS) and vaginal fungal infections, especially those caused by Candida albicans, are a significant problem in otherwise healthy women. The mucosal immune mechanisms that protect against microbial invasion of the female urogenital tract are not well understood, but are thought not to be dominated by systemic immunity. Since cell-mediated immunity (CMI) is the predominant host defense mechanism against many vaginal-associated pathogens (i.e., viruses, fungi, intracellular bacteria), it is critical that vaginal CMI mechanisms be identified. This proposal will focus on the local immune reactivity to C albicans, a clinically important opportunistic vaginal pathogen. Our primary effort will be to assess the influences of reproductive hormones (i.e., estrogen and progesterone) on local immune reactivity. Clinical experience indicates that elevations or alterations in reproductive hormones during the menstrual cycle, pregnancy, or while using contraceptives, influence the conversion of C. albicans from vaginal commensal to pathogen resulting in a high incidence of vulvovaginitis. In contrast, premenarchal and post-menopausal females rarely acquire vaginal C. albicans infections. We hypothesize that reproductive hormones influence local vaginal CMI, and specifically that elevations/imbalances in these hormones reduce local immunoprotective responses at the vaginal mucosa, resulting in increased susceptibility to vaginal C albicans infections. To test this hypothesis, we will use a novel human system whereby Candida-specific vaginal immune reactivity can be stimulated and CMI mediators (cytokines, etc.) in vaginal secretions can be measured during physiologic and pharmacologic hormonal states. Preliminary studies show that the intravaginal introduction of C. albicans skin test antigen during low hormone levels (follicular stage) effectively stimulates (challenges) local CMI (Thl-type cytokines) in vaginal secretions within 16-18 h. The long term goals are to use the information from these studies to identify potential hormone-associated periods of susceptibility to vaginal yeast infections and develop immunization/vaccination strategies to increase vaginal immune resistance.